Abstract
Thrombopoietin (TPO) regulates stem cell proliferation and maturation of megakaryocytes by activating the c-Mp1-receptor, a member of the hematopoietic cytokine family. As human platelets possess c-Mp1-receptors and supraphysiological concentrations of TPO trigger platelet aggregation and secretion, we searched for the signalling pathways through which the c-Mp1-receptor might activate platelets. A physiological concentration of TPO (20 ng/mL) did not trigger platelet functions, but increased their sensitivity to alpha-thrombin resulting in a 4-fold faster dense granule secretion. The effect of TPO was abolished by indomethacin and caused by synergism with signal generation by alpha-thrombin at the level of the cytosolic phospholipase A2 (cPLA2) pathway resulting in more arachidonate release, cPLA2 phosphorylation and thromboxane A2 formation. A similar synergism was seen at the level of extracellular signal-regulated kinase 2 (ERK2 or p42-MAPK). These data suggest, that TPO increases the sensitivity of platelets to alpha-thrombin by enhancing cPLA2 activation via the ERK2-cPLA2 pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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Carbazoles / pharmacology
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Cattle
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Cytoplasmic Granules / metabolism
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Drug Synergism
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Group IV Phospholipases A2
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Humans
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Imidazoles / pharmacology
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Indoles / pharmacology
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Indomethacin / pharmacology
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MAP Kinase Signaling System / drug effects*
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Maleimides / pharmacology
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 1 / physiology*
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Phospholipases A / physiology*
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Phospholipases A2
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Phosphorylation / drug effects
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Platelet Aggregation / drug effects*
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Protein Kinase C / antagonists & inhibitors
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Protein Processing, Post-Translational / drug effects
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Pyridines / pharmacology
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Serotonin / metabolism
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Serum Albumin, Bovine / pharmacology
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Thrombin / agonists*
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Thrombopoietin / pharmacology*
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Thromboxane A2 / biosynthesis
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p38 Mitogen-Activated Protein Kinases
Substances
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Carbazoles
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Enzyme Inhibitors
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Flavonoids
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Imidazoles
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Indoles
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Maleimides
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Pyridines
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Go 6976
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Serum Albumin, Bovine
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Serotonin
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Thromboxane A2
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Thrombopoietin
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Protein Kinase C
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Phospholipases A
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Group IV Phospholipases A2
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Phospholipases A2
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Thrombin
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bisindolylmaleimide I
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Ro 31-8220
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Indomethacin